The alpha-crystallins comprise a large fraction of the soluble protein in the vertebrate lens where they were, for many years, believed to function solely as structural proteins. This small family of crystallins is encoded by only 2 genes, the alphaA- and alphaB-crystallin genes and is collectively referred to as alpha-crystallin. They are related to the small heat shock proteins, and in vitro they exhibit molecular chaperon activity, autokinase activity, single stranded DNA binding activity, and interact with and affect the state of several cytoskeletal components. Alpha-Crystallin, especially alphaB-crystallin, has been shown to be a normal constituent of many non-lenticular tissues, and has been detected in cytoplasmic inclusion bodies found in several human pathological conditions. Toward understanding the major roles of alpha-crystallin in vivo, we have generated gene knockout mice. We are attempting to elucidate the in vivo functions of alphaA- and alphaB-crystallin 1) in lens development and morphogenesis; 2) in maintaining a stable, transparent lens throughout the life of an organism (i.e. preventing cataract); 3) in the non-lenticular tissues where they are normally present; and 4) in non-lenticular pathological conditions. We have previously generated mice which lackalphaA-crystallin, mice which lack alphaB-crystallin, and mice which are deficient in both alphaA- and alphaB-crystallin. Our research has demonstrated that neither alphaA-crystallin nor alphaB-crystallin is essential for survival or reproduction of the laboratory mouse. At a young age, mice lacking alphaA-crystallin develop cataract, characterized by intracellular inclusion bodies containing predominantly alphaB-crystallin, which eventually progresses to severe lens opacity. In mice lacking both alphaA- and alphaB-crystallin, the rate and extent of cataract formation are greatly enhanced, but inclusion bodies are not observed, suggesting a different mechanism of cataractogenesis. These mice are microphthalmic and exhibit severe cataract with a disorganized fiber cell compartment characterized by a sphere of degraded cells surrounding the lens nucleus and migration of newly differentiating fiber cells anteriorly, pushing the nucleus to the posterior of the lens and eventually rupturing the lens capsule. We have recently begun examining integrin expression patterns and lens capsule constituents in these mice to determine possible causes for failure of newly elongating fiber cells to migrate symmetrically. In contrast, mice lacking alphaB-crystallin alone exhibit no overt cataract. Young mice lacking alphaB-crystallin and the adjacent, concommitantly disrupted HSPB2 (MKBP) gene, exhibit no grossabnormalities, and histological analysis reveals signs of mild skeletal muscle cell damage and regeneration. With age, they develop kyphosis, a curvature of the spine, and severe muscle cell degeneration is evident in areas of the tongue, muscle cells associated with the axial skeleton, and, to a lesser extent, in select muscles of the limbs. Osteoarthritis is also evident in the vertebral column, possibly secondary to the muscle degeneration.